CLINICAL PHARMACOLOGY & THE1LAPEUTICS VOLUME 73, NUMBER 2 American Society for Clinical Pharmacology and 7'herapeutics P 3 9

PII-37 URINARY EXCRETION OF MIDAZOLAM, 1-Ott-

MIDAZOLAM AND 1-OH-MIDAZOLAM-GLUCURONIDE IN pRETERM NEONATES. S.N. de Wildt, MD, PhD, G. L. Kearns, PbarmD, D. J. Murry, PharmD, J. N. van den Anker, MD, PhD, Sophia Children's Hospital, Children's Mercy Hospital, Purdue Uni- versity, Children's National Medical Center, Rotterdam, Netherlands.

Background: Preterm infants demonstrate a decreased formation of 1-OH-midazolam (OHM) after nfidazolam (M) exposure due to low CYP3A4/5 activity. Their ability to glucuronidate OHM into 1-OH-midazolam-glucuronide (OHMG) has not been studied. To investigate this glucuronidation ability of preterm infants we assessed the urinary excretion of M, OHM and OHMG.

Methods: Urine was collected in 2-h portions during a 6-h period after intravenous or oral administration of 0.1 mg/kg M in 21 neo- nates (weight 0.9-1.35 kg, PNA 3-11 days, GA 26-34 wks). M, OHM and OHMG were determined in urine using GC-MS. OHM and OHMG concentrations were corrected for MW.

Results: The median values and ranges of M, OHM and OHMG (expressed as percentage of the M dose) excreted in the urine during the 6-h period were: for M 0.35% (0.00-1.35%), for OHM 0.04% (0.00-.14%) and for OHMG 1.3% (0.04-4.9%). Urinary excretion of 1-OH-midazolam-glucmonide increased significantly with advancing GA (r 0.6, p 0.01).

Conclusions: 1. These results show that preterm infants are able to glucuronidate OHM to OHMG.2. Preterm infants with a low GA have lower renal OHMG excretion than preterms with a higher GA. This is probably due to reduced glomerular infiltration rate and not to reduced OHMG formation, as the M/OHM ratio in plasma does not change with gestational age.

Clin Pharmacol Ther. 2001 Dec;70(6):525-31.

PII-38 IDENTIFYING THE BARRIERS TO CONDUCTING PHAR-

MACOKINETIC AND PHARMACODYNAMIC STUDIES IN PREGNANT WOMEN. K. Uhl, MD, M. Miller, PhD, DABT, RN, K. K. Chapman, D. L. Kennedy, RPh, MPH, US Food and Drug Administration, Rockville, MD.

Pregnant women are usually excluded from clinical trials unless the drug is being developed for a specific use that occurs only during pregnancy. Even in situations where pregnant women require thera- peutics, studies are rarely done. Yet, the physiology of pregnancy is likely to change the absorption, distribution and activity of many drugs. To collect useful dosing information for pregnant women in need of drug therapy, PK/PD studies were designed that enrolled pregnant women currently receiving medical treatment for hyperten- sion. Traditional PK and population PK designs were used to study pregnant women during the 2rid trimester, and 3rd trimester. Both studies will measure PK and PD parameters in the postpartum period to determine the baseline kinetics and dynamics of the medication in these women.

Although these studies involved minimal additional interventions for the pregnant woman, numerous concerns about fetal safety and maternal risk were raised. Recent changes in the human subject protection regulations will eliminate the need for paternal consent lbr some clinical studies involving pregnant women but pregnant women are still classified as a vulnerable population. These pilot studies helped to identify barriers and serve as a model for future clinical research involving pregnant women. Barriers to participation of women in clinical trials limit the quality and quantity of information available to practitioners treating pregnant women.

PII-39 REVIEW OF DRUG LABELING FOR INFORMATION RE-

GARDING LACTATION. K. Uht, MD, R. Peat, MS, T. Toigo, RPh, D. L. Kennedy, RPh, MPH, S. L. Kweder, MD, US Food and Drug Administration, Rockville, MD.

Breast milk is widely acknowledged to be the most complete form of nutrition for infants, with a range of benefits for infants' health, growth, immunity, and development. The American Academy of Pediatrics (AAP) considers breastfeeding to be "the ideal method of feeding and nurturing infants" and recommends that all women breastfeed until their child reaches one year of age. The Department of Health and Human Services in Healthy People 2010 targets to increase the percentage of mothers who breastfeed to 75% in the early postpartum period, 50% at 6 months, and 25% at 1 year. The Physicians' Desk Reference (PDR) is frequently used as a source of information for medication use during lactation.

Objectives: To review the PDR for labeling for nursing mothers and assess the availability of clinically relevant information.

Results: 1022 prescription drug labels were searched. 260 (25%) labels indicated drug excretion in human milk and/or effects in nursing infants and 160 (16%) labels contained information about excretion of drug in animals. Half of labels indicated that excretion in human milk was unknown and 88 labels (9%) included no statement for nursing mothers.

Conclusions: More information is needed in labeling to assist lactating women and clinicians with decision making regarding the use of drugs during lactation.

PII-40 STRUCTURE-ACTIVITY RELATIONSHIPS AS PREDIC-

TORS OF ADVERSE DRUG EVENTS (ADES). J. F. Knudsen~ PhD, MD, G. H. Sokol, MD, FCP and L. R. Cantilena, MD, PhD, Uniform Services University of the Health Sciences, Bethesda, MD.

Often a common pattern in drug development is not creation de

novo but rather exploitation of side effects of existing drugs, eg the sulfonamide series and the exploitation of their side effects that resulted in new kinds of drugs, ie the carbonic anhydrase inhibitors/ diuretics. Insightful recognition of the nature of ADEs may arise from knowledge of SARs. Methods FDA's Adverse Event Reporting System & MEDLINE were searched for ADEs associated with newly marketed antiepileptic drugs zonisamide (ZNS), topiramate (TPM), and the COX-2 inhibitor celecoxib, drugs with sulfonamide substitu- ents. ADEs were categorized; emphasis on metabolic events. Patient demographics, dosing, duration of treatment, concomitant drugs were summarized. Results Three cases (1/3 U.S.) of ~ NH 3 (140 mcg/dl) were identified with ZNS and one case associated with TPM. She had a + decballenge and + recballenge to TPM; the latter event charac- terized by j' NH 3 (254mcg/dl) & metabolic acidosis (MA). The incidence of hyperchtoremia and ~, Phos in celecoxib Rx patients >Pbo. Cases of MA, nephrolithiasis, and HCO 3 diuresis reported with AEDs. Conclusion We describe cases of acid-base disorders temporally related to drugs with similar structural components, ie the SOaNH z moiety. Understanding SARs/drug action may assist in predicting serious ADEs & potential cross-reactivity among medica- tions.